Cancer causing viruses may use MicroRNAs to alter Tumor Microenvironment

Cells infected with Kaposi's sarcoma-associated herpesvirus (KSHV) can deliver small molecules of genetic material (microRNAs) to nearby non-infected cells in order to reprogram their metabolism, facilitating enhanced growth of the infected cells. This finding, published in PLOS Pathogens, suggests a possible mechanism by which tumors regulate their microenvironment.

In cancer cells, metabolic pathways tend to be rewired to enable rapid proliferation and tumorgrowth. One such change is known as the Warburg effect—an alteration in the glucose breakdown process that provides energy for the cell. Previous research has suggested that cancer cells displaying the Warburg effect can also induce a similar “reverse Warburg” effect in adjacent cells.

To investigate the mechanism underlying the reverse Warburg effect, Ohad Yogev of University College London, U.K., and colleagues turned to KSHV. This virus can cause a type of cancer known as Kaposi’s sarcoma. Like other cancer-causing viruses, KSHV is known to hijack cellular metabolism, making it a useful tool to examine how cancer cells regulate their environment.

The researchers had previously shown that microRNAs produced in KSHV-infected cells are responsible for causing the Warburg effect in those cells. They also knew that thesemicroRNAs could be transported outside of infected cells in small sacks known as exosomes.

In the new study, the scientists infected primary lymphatic endothelial cells with KSHV and examined the effects using a variety of culturing and molecular techniques. They found that the infected cells use exosomes to transfer microRNAs to non-infected cells, where they induced a reverse Warburg effect. This metabolic reprogramming appeared to transform the non-infected cells into “feeder cells” that produced substances fueling the growth of the infected cells.

Additional lab work showed that cells infected with other herpesviruses, such as the Epstein-Barr virus, can also use microRNA transfer to influence the metabolism of nearby cells. These microRNAs are encoded by the viral genome and can be produced in infected cells without assembling full virus copies, allowing them to slip under the radar of the immune system.

Overall, these findings suggest that viruses and cancer cells use an exosome-based microRNA transfer mechanism to regulate their surrounding microenvironment and enhance their growth. Future research could explore ways to target this mechanism in order to combattumor growth.

“We identified a novel mechanism allowing oncogenic viruses as well as non-viral cancers to induce reverse Warburg effect by transferring their miRNAs in exosomes,” the authors explain. “This flow of genetic information allows cells to shape a specific metabolic niche that will favour their proliferation while staying hidden from the immune system.”

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